In toto understanding of organ function by integrated analysis of multicellular networks mediated by intercellular delivery of metabolites

• Project/Area Number: 17H06270
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Single-year Grants
• Research Field: General internal medicine and related fields
• Research Institution: Keio University
• Principal Investigator: ITOH Hiroshi 慶應義塾大学, 医学部(信濃町), 教授 (40252457)
• Co-Investigator(Kenkyū-buntansha): 宮下 和季 慶應義塾大学, 医学部(信濃町), 特任准教授 (50378759)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000); Fiscal Year 2019: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2018: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2017: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
• Keywords: 代謝産物 / 液性因子 / 細胞間送達 / 質量分析イメージング / 腸内細菌叢 / 母児連関 / 臓器機能 / 非感染性疾患 / 胎児発育 / 短鎖脂肪酸 / 臓器連関 / 無菌マウス / 糖尿病性腎臓病 / 代謝変容 / マスイメージング / メタボローム / 急性腎不全 / ATP / アデニンヌクレオチド / 腎臓 / 腎不全 / 多細胞間ネットワーク

Outline of Final Research Achievements

In this study, we aimed to understand the pathophysiology of non-communicable diseases (NCDs) from the alterations in intercellular delivery of metabolites. By utilizing novel technologies such as mass imaging analysis and metabolome, we clarified the significance of low-molecular weight metabolites for organ function. We pointed out the roles for metabolites derived from maternal microbiota in the development of obesity and diabetes of the offspring in mice. The novel understanding of organ function from the perspective of intercellular delivery of metabolites is different from existing approach of the molecular biology which analyzes molecular function in the cell. It has brought novel results with plenty of originality that are suitable for grant-in-aid for exploratory research.

Academic Significance and Societal Importance of the Research Achievements

これまでの医学研究では、臓器の構成要素の一つ一つに焦点を当て、分子生物学的手法に基づき、個々の分子の細胞内の役割を検討することで、臓器機能に関する知見を断片的に集積してきた。しかしながら、実際の臓器は多数の要素で構成され、それらは液性因子を介した、お互いのコミュニケーションが円滑に行われることで初めて機能を発揮し、細胞間分子送達の変調は、非感染性疾患の発症に直結する。本研究では、臓器および生体を構成する要素の有機的連携に着目し、代謝産物の送達を介した臓器内・臓器間の情報伝達により制御される、臓器・生体における多細胞間ネットワークの解析から、臓器機能ならびにその破綻病態の理解を目指す。

Research Products

• [Journal Article] Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice (2020)
  • Author(s): Kimura I, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, Aoki R, Isobe Y, Kashihara D, Inoue D, Inaba A, Takamura Y, Taira S, Kumaki S, Watanabe M, Ito M, Nakagawa F, Irie J, Kakuta H, Shinohara M, Iwatsuki K, Tsujimoto G, Ohno H, Arita M, Itoh H, Hase K.
  • Journal Title: Science Volume: 367 Issue: 6481 Pages: 8429-8429
  • DOI: 10.1126/science.aaw8429
  • Peer Reviewed / Open Access
• [Journal Article] Associations of birthweight and history of childhood obesity with beta cell mass in Japanese adults (2020)
  • Author(s): Sasaki H, Saisho Y, Inaishi J, Watanabe Y, Tsuchiya T, Makio M, Sato M, Kitago M, Yamada T, Itoh H
  • Journal Title: Diabetologia Volume: - Issue: 6 Pages: 1199-1210
  • DOI: 10.1007/s00125-020-05127-2
  • Peer Reviewed / Open Access
• [Journal Article] Association of glucose tolerance status with pancreatic β‐ and α‐cell mass in community‐based autopsy samples of Japanese individuals: The Hisayama Study (2020)
  • Author(s): Inaishi Jun、Saisho Yoshifumi、Hirakawa Yoichiro、Yoshida Daigo、Hata Jun、Mukai Naoko、Watanabe Yuusuke、Oda Yoshinao、Itoh Hiroshi、Ninomiya Toshiharu
  • Journal Title: Journal of Diabetes Investigation Volume: - Issue: 5 Pages: 1197-1206
  • DOI: 10.1111/jdi.13232
  • Peer Reviewed / Open Access
• [Journal Article] Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men (2020)
  • Author(s): Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H
  • Journal Title: Endocrine Journal Volume: 67 Issue: 2 Pages: 153-160
  • DOI: 10.1507/endocrj.EJ19-0313
  • NAID: 130007802884
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression (2020)
  • Author(s): Kodani Noriko、Nakae Jun、Kobayashi Masaki、Kikuchi Osamu、Kitamura Tadahiro、Itoh Hiroshi
  • Journal Title: iScience Volume: 23 Issue: 1 Pages: 100798-100798
  • DOI: 10.1016/j.isci.2019.100798
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Foxo in T Cells Regulates Thermogenic Program through Ccr4/Ccl22 Axis (2019)
  • Author(s): Kikuchi Tetsuhiro、Nakae Jun、Kawano Yoshinaga、Watanabe Nobuyuki、Onodera Masafumi、Itoh Hiroshi
  • Journal Title: iScience Volume: 22 Pages: 81-96
  • DOI: 10.1016/j.isci.2019.11.006
  • Peer Reviewed
• [Journal Article] Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides. (2019)
  • Author(s): Fujii K, Kubo A, Miyashita K, Sato M, Hagiwara A, Inoue H, Ryuzaki M, Tamaki M, Hishiki T, Hayakawa N, Kabe Y, Itoh H, Suematsu M.
  • Journal Title: JCI insight Volume: 4 Issue: 22 Pages: 124816-124816
  • DOI: 10.1172/jci.insight.124816
  • Peer Reviewed / Open Access
• [Journal Article] Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions (2019)
  • Author(s): Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I
  • Journal Title: Proc Natl Acad Sci USA Volume: 116 Issue: 47 Pages: 23813-23821
  • DOI: 10.1073/pnas.1912573116
  • Peer Reviewed / Open Access
• [Journal Article] Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids (2019)
  • Author(s): Miyamoto J, Igarashi M, Watanabe K, Karaki SI, Mukouyama H, Kishino S, Li X, Ichimura A, Irie J, Sugimoto Y, Mizutani T, Sugawara T, Miki T, Ogawa J, Drucker DJ, Arita M, Itoh H, Kimura I
  • Journal Title: Nat Commun Volume: 10 Issue: 1 Pages: 1-15
  • DOI: 10.1038/s41467-019-11978-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] β-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects. (2019)
  • Author(s): Tajima T, Yoshifuji A, Matsui A, Itoh T, Uchiyama K, Kanda T, Tokuyama H, Wakino S, Itoh H.
  • Journal Title: Kidney Int. Volume: 95 Issue: 5 Pages: 1120-1137
  • DOI: 10.1016/j.kint.2018.11.034
  • Peer Reviewed / Open Access
• [Journal Article] Decreased KAT5 Expression Impairs DNA Repair and Induces Altered DNA Methylation in Kidney Podocytes (2019)
  • Author(s): Hishikawa Akihito、Hayashi Kaori、Abe Takaya、Kaneko Mari、Yokoi Hideki、Azegami Tatsuhiko、Nakamura Mari、Yoshimoto Norifumi、Kanda Takeshi、Sakamaki Yusuke、Itoh Hiroshi
  • Journal Title: Cell Reports Volume: 26 Issue: 5 Pages: 1318-1332
  • DOI: 10.1016/j.celrep.2019.01.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy. (2019)
  • Author(s): Muraoka H, Hasegawa K, Sakamaki Y, Minakuchi H, Kawaguchi T, Yasuda I, Kanda T, Tokuyama H, Wakino S, Itoh H.
  • Journal Title: Cell Rep. Volume: 27(1) Issue: 1 Pages: 199-212
  • DOI: 10.1016/j.celrep.2019.03.024
  • Peer Reviewed / Open Access
• [Journal Article] Home-based Aerobic Exercise and Resistance Training in Peritoneal Dialysis Patients: A Randomized Controlled Trial (2019)
  • Author(s): Uchiyama Kiyotaka、Washida Naoki、Morimoto Kohkichi、Muraoka Kaori、Kasai Takahiro、Yamaki Kentaro、Miyashita Kazutoshi、Wakino Shu、Itoh Hiroshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2632-2632
  • DOI: 10.1038/s41598-019-39074-9
  • Peer Reviewed / Open Access
• [Journal Article] Pre-emptive medicine for hypertension and its prospects (2018)
  • Author(s): Itoh Hiroshi、Hayashi Kaori、Miyashita Kazutoshi
  • Journal Title: Hypertension Research Volume: 42 Issue: 3 Pages: 301-305
  • DOI: 10.1038/s41440-018-0177-3
  • Peer Reviewed
• [Journal Article] Exercise Capacity and Association with Quality of Life in Peritoneal Dialysis Patients (2018)
  • Author(s): Uchiyama Kiyotaka、Washida Naoki、Muraoka Kaori、Morimoto Kohkichi、Kasai Takahiro、Yamaki Kentaro、Miyashita Kazutoshi、Wakino Shu、Itoh Hiroshi
  • Journal Title: Peritoneal Dialysis International Volume: 39 Issue: 1 Pages: 66-73
  • DOI: 10.3747/pdi.2018.00075
  • Peer Reviewed
• [Journal Article] Organ memory: a key principle for understanding the pathophysiology of hypertension and other non-communicable diseases (2018)
  • Author(s): Itoh Hiroshi、Kurihara Isao、Miyashita Kazutoshi
  • Journal Title: Hypertension Research Volume: 41 Issue: 10 Pages: 771-779
  • DOI: 10.1038/s41440-018-0081-x
  • Peer Reviewed
• [Journal Article] Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization (2018)
  • Author(s): Mitsuishi Yuko、Shibata Hirotaka、Kurihara Isao、Kobayashi Sakiko、Yokota Kenichi、Murai-Takeda Ayano、Hayashi Takeshi、Jo Rie、Nakamura Toshifumi、Morisaki Mitsuha、Itoh Hiroshi
  • Journal Title: Molecular and Cellular Endocrinology Volume: in press Pages: 30017-30017
  • DOI: 10.1016/j.mce.2018.01.007
  • Peer Reviewed / Open Access
• [Journal Article] Intranasal vaccination against angiotensin II type 1 receptor and pneumococcal surface protein A attenuates hypertension and pneumococcal infection in rodents. (2018)
  • Author(s): Tatsuhiko Azegami, Yoshikazu Yuki, Kaori Hayashi, Akihito Hishikawa, Shin-ichi Sawada, Kazuya Ishige, Kazunari Akiyoshi, Hiroshi Kiyono, Hiroshi Itoh.
  • Journal Title: J Hypertens Volume: 36 (2) Issue: 2 Pages: 387-394
  • DOI: 10.1097/hjh.0000000000001519
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid (2017)
  • Author(s): Fujii Chikako、Miyashita Kazutoshi、Mitsuishi Masanori、Sato Masaaki、Fujii Kentaro、Inoue Hiroyuki、Hagiwara Aika、Endo Sho、Uto Asuka、Ryuzaki Masaki、Nakajima Motowo、Tanaka Tohru、Tamaki Masanori、Muraki Ayako、Kawai Toshihide、Itoh Hiroshi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-017-03917-0
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation (2017)
  • Author(s): Tamaki M, Miyashita K, Hagiwara A, Wakino S, Inoue H, Fujii K, Fujii C, Endo S, Uto A, Mitsuishi M, Sato M, Doi T, Itoh H.
  • Journal Title: Endocrine Journal Volume: 64 Issue: Suppl. Pages: S47-S51
  • DOI: 10.1507/endocrj.64.S47
  • NAID: 130007307942
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials. (2017)
  • Author(s): Itoh H, Kurihara I, Miyashita K, Tanaka M.
  • Journal Title: Hypertens Res. Volume: 40 Issue: 6 Pages: 526-534
  • DOI: 10.1038/hr.2016.192
  • Peer Reviewed / Open Access
• [Presentation] 急性虚血性腎障害におけるフェブキスソタットによるATPブーストを介した腎保護メカニズムのマスイメージングを用いた可視化解析 (2018)
  • Author(s): 藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 伊藤裕
  • Organizer: 第41回日本高血圧学会総会
• [Presentation] A semi-quantitative mass imaging technique revealed region-specific alteration of adenylates in the murine kidney after transient ischemia and reno-protective effect of febuxostat by ameliorating ATP levels in the cortex. (2018)
  • Author(s): 藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 伊藤裕
  • Organizer: 第61回日本腎臓学会総会
• [Presentation] キサンチンオキシダーゼ阻害による虚血腎保護メカニズムのマスイメージングを用いた可視化解析 (2018)
  • Author(s): 藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 伊藤裕
  • Organizer: 第91回日本内分泌学会総会
• [Presentation] Febuxostat exerted reno-protective effects after transient ischemia by promoting ATP recovery in the cortex: visualization of renal adenine nucleotides by an imaging mass-spectrometry technique (2018)
  • Author(s): K. Miyashita, K. Fujii, A. Kubo, M. Sato, A. Hagiwara, H. Inoue, M. Suematsu, H. Itoh
  • Organizer: 27th Scientific Meeting of International Society of Hypertension,
  • Int'l Joint Research
• [Presentation] A mass imaging technique revealed a reno-protective effect of the xanthine oxidase inhibitor febuxostat in the ischemic kidney by promoting ATP recovery in the cortex (2018)
  • Author(s): K. Miyashita, K. Fujii, A. Kubo, M. Sato, A. Hagiwara, H. Inoue, M. Suematsu, H. Itoh
  • Organizer: 28th Scientific Meeting of European Society of Hypertension
  • Int'l Joint Research
• [Presentation] A SEMI-QUANTITAIVE IMAGING MASS SPECTROMETRY REVEALED THE RENO-PROTECTIVE EFFECT OF FEBUXOSTAT IN THE ISCHEMIC KIDNEY BY PROMOTING ATP RECOVERY IN THE CORTEX. (2018)
  • Author(s): K. Miyashita, K. Fujii, A. Kubo, M. Sato, A. Hagiwara, H. Inoue, M. Suematsu, H. Itoh
  • Organizer: 55th ERA-EDTA congress
  • Int'l Joint Research
• [Presentation] マスイメージングによる腎代謝産物の可視化と皮髄境界アデノシン集積の意義の解析 (2017)
  • Author(s): 1.宮下 和季, 藤井 健太郎, 久保 亜紀子, 佐藤 正明, 末松 誠, 伊藤 裕
  • Organizer: 第53回高血圧関連疾患モデル動物学会
  • Invited
• [Presentation] 腎皮髄境界アデノシンによる虚血腎保護効果の検討 (2017)
  • Author(s): 4.藤井 健太郎, 宮下 和季, 久保 亜紀子, 佐藤 正明, 萩原 あいか, 井上 博之, 竜崎 正毅, 末松 誠, 伊藤 裕
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] Novel treatment of chronic kidney disease through regulation of adenylate metabolism (2017)
  • Author(s): 宮下 和季, 藤井 健太郎, 伊藤 裕
  • Organizer: Premium Hypertension Conference 2017
  • Invited
• [Presentation] 腎皮髄境界アデノシン集積の虚血腎における保護的役割の可視化解析 (2017)
  • Author(s): 11.藤井 健太郎, 宮下 和季, 久保 亜紀子, 佐藤 正明, 萩原 あいか, 井上 博之, 竜崎 正毅, 末松 誠, 伊藤 裕
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] ADENOSINE A2 RECEPTORS ARE INDISPENSABLE FOR THE MAINTANANCE OF RENAL BLOOD FLOW UNDER ACUTE ISCHEMIA. (2017)
  • Author(s): 6.K. Fujii, K. Miyashita, A. Kubo, M. Sato, A. Hagiwara, H. Inoue, M. Suematsu, H. Itoh
  • Organizer: 54th ERA-EDTA congress
  • Int'l Joint Research